There is strong experimental evidence that the epidermal growth factor receptor (EGFR) signal transduction pathway plays an important role as a cell survival mechanism and to sustain the growth of certain epithelial malignancies. EGFR is overexpressed in about 60 percent of non-small cell lung cancer (NSCLC) tumors. C225 is a humanized monoclonal antibody that specifically inhibits EGFR function by competing with EGF for binding to EGFR, thus resulting in cell growth inhibition. C225 has been shown to specifically sensitize tumors expressing EGFR to the effects of a variety of cytotoxic agents in in vivo experimental systems. There is also now emerging clinical evidence that C225 can sensitize cisplatin-resistant head and neck tumors to cisplatin. Neoadjuvant chemotherapy followed by surgical resection has been shown to improve the survival of patients with stage IIIA NSCLC in three separate randomized trials. However, the pathological complete remission rate with the regimens used ranges between 5 and 11 percent. It is reasonable to assume that a neoadjuvant regimen that would result in a higher rate of pathological complete response would further improve the survival of these patients. In this proposal, we will test the hypothesis that C225 synergizes with taxanes and platinum drugs in NSCLC tumors that have an activated EGFR signal transduction pathway. For that purpose: 1) we will study the antitumor activity of taxane/platinum +/- C225 in a series of human NSCLC heterotransplants in nude mice and will identify the molecular, determinants of synergism; and 2) we will conduct a Phase II clinical study of neoadjuvant taxane/platinum + C225 in patients with stage IIIA NSCLC tumors using a 20 percent pathological complete response as primary endpoint. Entry criteria for the clinical study will include tumors expressing the molecular determinants of synergism identified under number 1. In the context of the clinical study, we will correlate the degree of pathological response with the pre- and post-therapy EGFR activation status of the tumors. The results of the studies proposed will indicate the potential of this combination in the treatment of NSCLC, identify the specific subsets of tumors that are more likely to respond to this combination, and eventually justify the definitive testing of the hypothesis in a randomized clinical trial.